1. Field of the Invention
The present invention relates to the preparation of cephalomannine epoxide and 10-DATB-epoxide from the precursors cephalomannine and 10-deacetyl taxol B (10-DATB), respectively. Specifically, the present invention relates to novel active antitumor agents that are formed when the tiglate structure located on the side chain of the aforementioned precursors is converted into an epoxide.
2. Description of the State of Art
Between the years 1958 and 1980, extracts of over 35,000 plant species were tested for anticancer activity as part of an NCI-sponsored program. Chemists Monroe E. Wall and M. C. Wani first isolated a crude extract concentrate from yew tree (Taxus brevifolia) bark and wood samples in 1963. Initial screening showed the extract to be a potential anticancer agent, being very active against an unusually wide range of rodent cancers. Isolation of the active agent in the crude extract took several years due to the very low concentrations of the agent present in the plants. The active agent was identified, the structure determined and the compound, in 1971, was named taxol, generically referred to as paclitaxel (1). ##STR2##
The naturally occurring diterpenoid, paclitaxel (1), is one of the most exciting discoveries in the field of cancer chemotherapy. In 1979, Susan B. Horwitz and co-workers established that, while paclitaxel was an antimiotic inhibitor, the mechanism was unique in that it stabilizes microtubules and inhibits depolymerization back to tubulin; this was quite the opposite effect of other antimiotic agents which all bind to soluble tubulin and inhibit the polymerization of tubulin to form microtubules. See, Nature 227:655-667 (1979). Thus, taxol increases the time required for cell division which in turn inhibits tumor activity.
Since the discovery of paclitaxel, over one hundred compounds having the taxane skeleton have been isolated from various Taxus species, listed below are but a few of the representative structures of the more notable taxol analogues. ##STR3##
Despite paclitaxel's excellent activity in model tumor systems, research progressed at a rather a slow pace and its development was fraught with many obstacles including scarcity of the drug (owing to low abundance of Yew tissue), extremely low aqueous solubility, and toxicities. Problems in drug supply have largely been alleviated, not only as a result of more efficient collection and extraction of plant material, but also because of the progress made in the complete and semi-synthesis of the compound paclitaxel; however, the extremely low aqueous solubility and toxicity obstacles remain more difficult to overcome.
Paclitaxel is a complex diterpenoid which comprises of a bulky, fused ring system and an extended side chain at the C-13 position that is required for activity. This complex structure further contains 11 chiral centres with 2048 possible diastereoisomeric forms. Relatively hydrophilic domains exist in the molecule around the vicinity of the C-7 through C-10 and C-1' through C-2' positions. However, hydrophobic domains of the taxane backbone and side chain contribute to the overall poor aqueous solubility of the compound. In order to administer human doses in a reasonable volume, paclitaxel is currently formulated for clinical use in a mixture of anhydrous ethanol and polyethoxylated castor oil (Cremophor EL.RTM.), a clear, oily, viscous, yellow surfactant. In addition to the potential problems of physical instability, the most significant problem with the current clinical paclitaxel formulation is that the Cremophor EL.RTM. vehicle possesses pharmacological activity. While a variety of drugs are administered in Cremophor EL.RTM., the dose of Cremophor EL.RTM. that accompanies a dose of paclitaxel is the highest for any marketed drug. Cremophor EL.RTM. has been observed to cause serious or fatal hypersensitivity episodes, and vehicle toxicity may be largely responsible for fatal or life-threatening anaphylactoid reactions observed upon rapid infusion of paclitaxel into animals or humans.
In light of the serious risks associated with the current intravenous formulations of paclitaxel, efforts to develop safe, convenient, and efficacious paclitaxel formulations are ongoing. However, the majority of approaches underway to solve the problems associated with paclitaxel are the synthesis and evaluation of a second generation of paclitaxel analogues.
10-deacetylbaccatin III (2) and baccatin III (3) ##STR4## EQU 10-deacetyl baccatin III, R=H (2) EQU baccatin III, R=Ac (3)
are diterpenes that are more readily available than paclitaxel and are known synthetic precursors of paclitaxel and its analogues. Their structural complexity is less than that of paclitaxel's and therefore, 10-deacetylbaccatin III (2) and baccatin III (3) are also valuable starting materials for structural modifications at the diterpene part of the paclitaxel molecule.
10-deacetylbaccatin III was used as the starting material for the semisynthetic compound docetaxel (4) commonly referred to as Taxotere.RTM., developed by French researchers from the Institut de Chemie de Substances Naturelles and Rhone-Poulenc Rorer in 1981. ##STR5## The lateral side chain located at C-13 position, which is responsible for its cytoxic effect, is added chemically. Docetaxel differs structurally from paclitaxel at the C-10 position on the baccatin ring and at the C-3' position on the lateral side chain. See, "Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substitueants and Variable C-2' Configuration," J. Med. Chem., 34:1176-1184 (1991); "Relationships between the Structure of Taxol Analogues and Their Antimitotic Activity," J. Med. Chem., 34:992-998 (1991). Docetaxel is twice as potent an inhibitor of microtubule depolymerization as paclitaxel. The in vitro cytotoxicity of docetaxel in murine and human tumor cell lines and its in vivo preclinical activity in murine and human xenografts have been impressive. Docetaxel has displayed higher cytoxic activity than other antineoplastic agents such as paclitaxel, cisplatin, cyclophosphamide, and doxorubicin against the same tumor models. While docetaxel is a promising antitumor agent with a broad spectrum it, like paclitaxel, suffers low aqueous solubility. The fact remains however, that a potent analogue of paclitaxel having promising activity was developed by making a simple side chain modifications at the 3' amide. Encouraged by this exciting result other researchers began modifications to each position of the diterpene core hoping to develop a structural analogue of paclitaxel which overcomes the problems associated with paclitaxel; however, to date, non have been developed.
There is still a need, therefore, for developing structural analogues of paclitaxel which have less formulation problems and equivalent or greater potency than that of paclitaxel.